Cu(II) Mediated 1,4-Conjugate Addition of Boronic Acids and Indoles to VBP Leading Bisphosphonates as Potential Anti-Resorption Bone Drugs

Thanks to their structural similarity with pyrophosphate, bisphosphonates (BPs) ensure specific bone targeting [1] and are widely employed as drugs for the treatment of bone disorders. New recent studies demonstrated the cellular activity of BP acting as potent inhibitors of specific enzymes [2] thus leading to osteoclast inactivation. Herein we present a straightforward synthesis of gem-BP bearing different alkyl, aryl and indolyl derivatives in the -position through Cu(II) mediated conjugate addition of alkyl and aryl boronic acids as well as indoles to VBP. While boronic acid addition proceeds much better in the non-coordinating solvent toluene, indole addition can be performed either in DCE as well as in water with SDS under micellar conditions leading to comparable efficiency. This efficient and versatile synthesis of BPs allowed the preparation of several BP tetraethyl esters that were transformed into the corresponding bisphosphonic acids that are currently under investigation to assess their activity in the inhibition of the osteoclast activity.